Trimethylamine N-oxide Aggravates Thoracic Aortic Aneurysm by Inhibiting Axl to Promote Vascular Smooth Muscle Cell Dysfunction.

Abstract

Thoracic aortic aneurysm (TAA) is a life-threatening condition that currently lacks an effective therapeutic strategy. Phenotypic switching in vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) degradation are considered to be among the causes of TAA development. Trimethylamine N-oxide (TMAO) is a gut microbial metabolite that has been associated with the increased risk of cardiovascular diseases. However, its general association with TAA remains unclear. Therefore, the present study aimed to assess the possible role of TMAO in TAA development. In the mouse TAA model, TMAO exacerbates aortic dilation and degeneration, promoting the development of thoracic aortic aneurysm. Furthermore, TMAO was observed to impair murine cardiac function. In vitro, it was demonstrated that TMAO inhibited proliferation whilst promoting migration and apoptosis in VSMCs. RNA-sequence analysis of TMAO targets subsequently identified Axl and a cohort of genes associated with extracellular matrix signaling. Mechanistically, it was found that TMAO inducing a shift from a contractile to a synthetic phenotype by inhibiting Axl. Overexpressing Axl suppresses this transition. In summary, TMAO worsens TAA progression by impairing vascular smooth muscle cell function, and restoring Axl expression can counteract the phenotypic shift caused by high TMAO levels. Thus, targeting the TMAO-Axl regulatory axis could be a therapeutic strategy for TAA patients with elevated TMAO expression.